SNCAIP

Summary

SNCAIP (synuclein alpha interacting protein, HGNC:11139) is a protein-coding gene on chromosome 5q23.2, encoding Synphilin-1 (Q9Y6H5). Isoform 2 inhibits the ubiquitin ligase activity of SIAH1 and inhibits proteasomal degradation of target proteins.

This gene encodes a protein containing several protein-protein interaction domains, including ankyrin-like repeats, a coiled-coil domain, and an ATP/GTP-binding motif. The encoded protein interacts with alpha-synuclein in neuronal tissue and may play a role in the formation of cytoplasmic inclusions and neurodegeneration. A mutation in this gene has been associated with Parkinson’s disease. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 9627 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 162 total
• Phenotypes (HPO): 30
• Druggable target: yes
• MANE Select transcript: NM_005460

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11139
Approved symbol	SNCAIP
Name	synuclein alpha interacting protein
Location	5q23.2
Locus type	gene with protein product
Status	Approved
Aliases	SYPH1
Ensembl gene	ENSG00000064692
Ensembl biotype	protein_coding
OMIM	603779
Entrez	9627

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 28 protein_coding, 9 nonsense_mediated_decay, 2 retained_intron

ENST00000261367, ENST00000261368, ENST00000395466, ENST00000395469, ENST00000506272, ENST00000508017, ENST00000508681, ENST00000509023, ENST00000509154, ENST00000509652, ENST00000510003, ENST00000510658, ENST00000512146, ENST00000512385, ENST00000513719, ENST00000514467, ENST00000514497, ENST00000515215, ENST00000542191, ENST00000893275, ENST00000893276, ENST00000893277, ENST00000893278, ENST00000893279, ENST00000893280, ENST00000893281, ENST00000893282, ENST00000928739, ENST00000954318, ENST00000954319, ENST00000954320, ENST00000954321, ENST00000954322, ENST00000954323, ENST00000954324, ENST00000954325, ENST00000954326, ENST00000954327, ENST00000954328

RefSeq mRNA: 8 — MANE Select: NM_005460 NM_001242935, NM_001308100, NM_001308105, NM_001308106, NM_001308107, NM_001308108, NM_001308109, NM_005460

CCDS: CCDS4131, CCDS78054

Canonical transcript exons

ENST00000261368 — 11 exons

Exon	Start	End
ENSE00001892807	122463491	122464219
ENSE00002051766	122312237	122312284
ENSE00003472079	122444563	122444732
ENSE00003520951	122425352	122425531
ENSE00003530615	122403793	122403865
ENSE00003553369	122422868	122423739
ENSE00003601736	122431969	122432082
ENSE00003643812	122440629	122440754
ENSE00003663246	122449845	122449937
ENSE00003664257	122391089	122391191
ENSE00003789824	122450533	122451601

Expression profiles

Bgee: expression breadth ubiquitous, 240 present calls, max score 97.64.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0228 / max 67.7978, expressed in 573 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58207	0.8793	383
58208	0.5994	304
58206	0.2719	121
58204	0.1411	67
58205	0.1310	61

Top tissues by expression

275 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.64	gold quality
ganglionic eminence	UBERON:0004023	95.95	gold quality
germinal epithelium of ovary	UBERON:0001304	94.00	gold quality
periodontal ligament	UBERON:0008266	91.63	gold quality
endometrium	UBERON:0001295	90.97	gold quality
parietal pleura	UBERON:0002400	90.89	gold quality
embryo	UBERON:0000922	90.45	gold quality
stromal cell of endometrium	CL:0002255	90.21	gold quality
epithelium of bronchus	UBERON:0002031	89.57	gold quality
bronchial epithelial cell	CL:0002328	89.32	gold quality
myometrium	UBERON:0001296	89.25	gold quality
uterus	UBERON:0000995	89.21	gold quality
calcaneal tendon	UBERON:0003701	89.21	gold quality
sperm	CL:0000019	89.15	gold quality
decidua	UBERON:0002450	88.95	gold quality
bronchus	UBERON:0002185	88.93	gold quality
ovary	UBERON:0000992	88.83	gold quality
right ovary	UBERON:0002118	88.32	gold quality
left ovary	UBERON:0002119	88.23	gold quality
pleura	UBERON:0000977	87.69	gold quality
body of uterus	UBERON:0009853	87.07	gold quality
endocervix	UBERON:0000458	86.91	gold quality
male germ cell	CL:0000015	86.83	silver quality
palpebral conjunctiva	UBERON:0001812	86.70	gold quality
oviduct epithelium	UBERON:0004804	86.59	gold quality
choroid plexus epithelium	UBERON:0003911	86.25	gold quality
cervix squamous epithelium	UBERON:0006922	85.91	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.88	gold quality
uterine cervix	UBERON:0000002	85.41	gold quality
tendon	UBERON:0000043	85.24	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

45 targeting SNCAIP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3617-3P	99.98	67.86	918
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-5693	99.24	66.67	1106
HSA-MIR-499A-3P	99.18	69.20	1392

Literature-anchored findings (GeneRIF, showing 36)

• The amino acid sequence of synphilin-1 shows extensive homology with its human counterpart, especially in regions containing ankyrin-like motifs and the coiled-coil domain. Expression of mouse synphilin-1 in tissues is similar to its human counterpart. (PMID:11958831)
• results suggest that synphilin-1 has an important role in the formation of aggregates and cytotoxicity in Parkinson disease and that Dorfin may be involved in the pathogenic process by ubiquitylation of synphilin-1 (PMID:12750386)
• a causative role of the R621C mutation in the synphilin-1 gene in Parkinson’s disease (PMID:12761037)
• Changes in synuclein expression presage neurodegeneration in a Drosophila model of Parkinson disease. (PMID:12915459)
• Siah-1 was found to abrogate the inhibitory effects of synphilin-1 on dopamine release (PMID:14506261)
• role of aggresomes in cell viability was addressed in the context of over-expressing alpha-synuclein and its interacting partner synphilin-1 (PMID:14627698)
• Casein kinase II (CKII) phosphorylates synphilin-1; beta subunit of this enzyme complex binds to synphilin-1. CKII-mediated phosphorylation of synphilin-1, rather than alpha-synuclein, modulates the aggregation into inclusion bodies. (PMID:14645218)
• role of synphilin-1 in synaptic function and protein degradation and in the molecular mechanisms leading to neurodegeneration in Parkinson disease (PMID:15322916)
• Parkin is a dual-function ubiquitin ligase. K63-linked ubiquitination of synphilin-1 by parkin may be involved in the formation of Lewy body inclusions associated with Parkinson disease. (PMID:15728840)
• We confirm that synphilin-1 and parkin are components of majority of Lewy Bodies in Parkinson’s disease and that both proteins are susceptible to proteasomal degradation. (PMID:15894486)
• GSK3beta modulates synphilin-1 ubiquitylation and cellular inclusion formation by SIAH (PMID:16174773)
• Synphilin-1A may contribute to neuronal degeneration in alpha-synuclein mutations and provides insights into the role of inclusion bodies in neurodegenerative disorders. (PMID:16595633)
• These results suggest that NUB1 indeed targets synphilin-1 to the proteasome for its efficient degradation, which, because of the resultant reduction in synphilin-1, suppresses the formation of synphilin-1-positive inclusions. (PMID:16877356)
• a novel specific interaction of synphilin-1 with the regulatory proteasomal protein S6 ATPase (tbp7) in aggresome-like intracytoplasmic inclusions (PMID:17327361)
• These findings suggest that parkin and synphilin-1 isoform expression changes play a significant role in the pathogenesis of LB diseases. (PMID:17467279)
• review:Isoform Synphilin-1A inclusions recruit both alpha-synuclein and synphilin-1. Aggregation of synphilin-1 and synphilin-1A seems to be protective to cells (PMID:17982729)
• specific effects of C621 mutant synphilin-1 on gene expression that correlate with its role as a susceptibility factor in Parkinson’s disease (PMID:18292964)
• All four alpha-synuclein isoforms were affected in dementia with LB (Lewy bodies), most parkin transcript variants in common LB disease, and all synphilin-1 isoforms in Parkinson disease. (PMID:18335262)
• We found no evidence for association between genetic variability in synphilin-1 and Parkinson’s disease (PMID:18366718)
• translocation to aggresomes required a special aggresome-targeting signal within the sequence of synphilin 1, an ankyrin-like repeat domain. (PMID:18635553)
• Synphilin-1 might be involved in motor function, and its accumulation in the central nervous system can cause motor impairments. (PMID:18782602)
• synphilin-1A has a novel role as a regulator of SIAH activity, modulating alpha-synuclein, and formation of Lewy body-like inclusions (PMID:19224863)
• Data show that periphilin displays an overlapping expression pattern with synphilin-1 in cellular and animal models and in Lewy bodies of Parkinson’s disease (PD) patients, and support involvement of periphilin in PD. (PMID:19730898)
• alpha-synuclein-synphilin-1 interaction significantly promotes the formation of cytoplasmic alpha-synuclein inclusions, which may have implications for Lewy body formation in neural cells (PMID:19762560)
• expression of synphilin-1 shortens N1E-115 cell division doubling time, promotes neurite outgrowth, and protects against Rotenone-induced toxicity; synphilin-1 displays a neurotrophic effect in vitro, may play a neuroprotective role in Parkinson’s disease (PMID:19857556)
• Knockdown of Herp gene unexpectedly facilitated the degradation of synphilin-1, and improved cell viability during proteasomal inhibition. (PMID:20604806)
• Neuronal survival factor MEF2D is decreased in human and experimental Parkinson’s disease, a decrease that is specifically associated with alpha-synuclein accumulation and aggregation. (PMID:20816781)
• Although serine-129 phosphorylation of alpha-synuclein facilitates tubulin polymerization promoting protein (TPPP)-mediated alpha-SYN oligomerization, this modification does not seem to play an inevitable role in the early step of alpha-SYN oligomer formation. (PMID:20849899)
• Synphilin-1 inhibits alpha-synuclein degradation by the proteasome. (PMID:21103907)
• Mutation screening of SNCAIP identifies novel sequence variants using a bioinformatic approach; further studies are necessary to determine their possible functional consequences in South African patients with Parkinson’s disease. (PMID:21344240)
• Overexpression of SP1 in neurons, but not peripheral cells, increased the body weight of flies compared with that of non-transgenic controls. SP1 increased food intake but did not affect locomotor activity (PMID:22828940)
• Overexpression of human synphilin-1 in mice resulted in hyperphagia and obesity. (PMID:24829096)
• Synphilin-1 binds ATP, but not CTP. (PMID:25545246)
• Differential expression of synphilin-1 isoforms (and alpha-synuclein and parkin) was found in multiple system atrophy brains compared to control brain. (PMID:26465922)
• results indicated that synphilin-1 may play neuroprotective roles in Parkinson Disease pathogenesis by inhibiting ROS production and apoptosis. (PMID:30316984)
• Exploring Structural Insights of Abeta42 and alpha-Synuclein Monomers and Heterodimer: A Comparative Study Using Implicit and Explicit Solvent Simulations. (PMID:38700150)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sncaip	ENSDARG00000100198
mus_musculus	Sncaip	ENSMUSG00000024534
rattus_norvegicus	Sncaip	ENSRNOG00000018254

Protein

Protein identifiers

Synphilin-1 — Q9Y6H5 (reviewed: Q9Y6H5)

Alternative names: Alpha-synuclein-interacting protein

All UniProt accessions (11): Q9Y6H5, D6R9G8, D6RBR2, D6RD29, D6REC1, D6RFL3, D6RHX3, Q6L980, Q6L981, Q6L982, Q6L983

UniProt curated annotations — full annotation on UniProt →

Function. Isoform 2 inhibits the ubiquitin ligase activity of SIAH1 and inhibits proteasomal degradation of target proteins. Isoform 2 inhibits autoubiquitination and proteasomal degradation of SIAH1, and thereby increases cellular levels of SIAH. Isoform 2 modulates SNCA monoubiquitination by SIAH1.

Subunit / interactions. Homodimer. Heterodimer of isoform 1 and isoform 2. Interacts with SIAH1, SIAH2, SNCA, RNF19A and PRKN. Isoform 2 has a strong tendency to form aggregates and can sequester isoform 1.

Subcellular location. Cytoplasm.

Tissue specificity. Detected in brain (at protein level). Widely expressed, with highest levels in brain, heart and placenta.

Post-translational modifications. Ubiquitinated; mediated by SIAH1, SIAH2 or RNF19A and leading to its subsequent proteasomal degradation. In the absence of proteasomal degradation, ubiquitinated SNCAIP accumulates in cytoplasmic inclusion bodies. Isoform 2 is subject to limited ubiquitination that does not lead to proteasomal degradation.

Disease relevance. Parkinson disease (PARK) [MIM:168600] A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Miscellaneous. Constructs encoding portions of SNCA and SNCAIP co-transfected in mammalian cells promote cytosolic inclusions resembling the Lewy bodies of Parkinson disease. Coexpression of SNCA, SNCAIP, and PRKN result in the formation of Lewy body-like. ubiquitin-positive cytosolic inclusions. SNCAIP isoform 2 is particularly aggregation-prone. Familial mutations in PRKN disrupt the ubiquitination of SNCAIP and the formation of the ubiquitin-positive inclusions. These results provide a molecular basis for the ubiquitination of Lewy body-associated proteins and link PRKN and SNCA in a common pathogenic mechanism through their interaction with SNCAIP.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9Y6H5-1	1, 1a	yes
Q9Y6H5-2	2, Synphilin-1A
Q9Y6H5-3	3
Q9Y6H5-4	4, 1b
Q9Y6H5-5	5
Q9Y6H5-6	6, 1c

RefSeq proteins (8): NP_001229864, NP_001295029, NP_001295034, NP_001295035, NP_001295036, NP_001295037, NP_001295038, NP_005451* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR032027	SNCAIP_SNCA-bd	Domain
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR040133	SNCAIP	Family

Pfam: PF12796, PF16700

UniProt features (42 total): compositionally biased region 8, splice variant 7, repeat 6, region of interest 6, sequence conflict 6, sequence variant 4, mutagenesis site 2, chain 1, coiled-coil region 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2KES	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6H5-F1	51.98	0.17

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (2):

Position	Phenotype
79	decreases interaction with siah1 and formation of cytoplasmic inclusion bodies; when associated with n-81.
81	decreases interaction with siah1 and formation of cytoplasmic inclusion bodies; when associated with n-79.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-977225	Amyloid fiber formation
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 253 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, GOBP_NEUROTRANSMITTER_TRANSPORT, FOXO4_01, FOXO1_01, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, USF_C, FOXD3_01, GOBP_CELL_CELL_SIGNALING, GOBP_DOPAMINE_METABOLIC_PROCESS, MYCMAX_01, HFH8_01

GO Biological Process (4): cell death (GO:0008219), dopamine metabolic process (GO:0042417), regulation of neurotransmitter secretion (GO:0046928), regulation of inclusion body assembly (GO:0090083)

GO Molecular Function (3): ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (7): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), synaptic vesicle (GO:0008021), cytoplasmic ribonucleoprotein granule (GO:0036464), presynaptic membrane (GO:0042734), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
presynapse	2
cellular process	1
catecholamine metabolic process	1
neurotransmitter secretion	1
modulation of chemical synaptic transmission	1
regulation of neurotransmitter transport	1
regulation of secretion by cell	1
regulation of cellular component biogenesis	1
regulation of cellular component organization	1
inclusion body assembly	1
ubiquitin-like protein ligase binding	1
protein binding	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
exocytic vesicle	1
ribonucleoprotein granule	1
synaptic membrane	1
somatodendritic compartment	1
cell body	1

Protein interactions and networks

STRING

1304 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SNCAIP	SNCA	P37840	998
SNCAIP	PRKN	O60260	997
SNCAIP	SIAH1	Q8IUQ4	873
SNCAIP	GPR37	O15354	797
SNCAIP	SLC6A3	Q01959	749
SNCAIP	SEPTIN5	Q99719	713
SNCAIP	PARK7	Q99497	701
SNCAIP	PINK1	Q9BXM7	696
SNCAIP	LRRK2	Q5S007	689
SNCAIP	AIMP2	Q13155	669
SNCAIP	SNCB	Q16143	655
SNCAIP	HSPA4	P34932	650
SNCAIP	STUB1	Q9UNE7	646
SNCAIP	SYT11	Q9BT88	645
SNCAIP	RNF19A	Q9NV58	642

IntAct

63 interactions, top by confidence:

A	B	Type	Score
SNCA	SNCAIP	psi-mi:“MI:0407”(direct interaction)	0.830
SNCAIP	SNCA	psi-mi:“MI:0407”(direct interaction)	0.830
SNCA	SNCAIP	psi-mi:“MI:0403”(colocalization)	0.830
SNCA	SNCAIP	psi-mi:“MI:0915”(physical association)	0.830
SNCAIP	SNCA	psi-mi:“MI:0915”(physical association)	0.830
SNCAIP	SNCA	psi-mi:“MI:0403”(colocalization)	0.830
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740
SNCAIP	SNCAIP	psi-mi:“MI:0407”(direct interaction)	0.680
SNCAIP	PPHLN1	psi-mi:“MI:0403”(colocalization)	0.460
SNCAIP	PPHLN1	psi-mi:“MI:0915”(physical association)	0.460

BioGRID (89): Pphln1 (Affinity Capture-Western), SNCA (Two-hybrid), SNCAIP (Biochemical Activity), SNCAIP (Affinity Capture-MS), SNCAIP (Affinity Capture-Western), KALRN (Two-hybrid), KALRN (Affinity Capture-Western), PPP1CA (Two-hybrid), PPP1CC (Two-hybrid), PPP1CC (Far Western), PPP1CA (Co-localization), PPP1CC (Co-localization), SNCAIP (Affinity Capture-Western), SNCAIP (Affinity Capture-Western), SNCAIP (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8HBI7, A0A1L8HJK9, A0A1L8HTT5, A6NP61, A8T6P4, C0SPG1, C3VD30, F1N4E5, K7SGN7, O35144, O35253, O70240, O88406, O88566, Q15554, Q1XFL1, Q3ZC82, Q4KLH3, Q5HZN9, Q5JTV8, Q5PQX1, Q5R7A3, Q62315, Q68DK7, Q6P1H6, Q6PDM1, Q6PG95, Q6ZPF3, Q76N89, Q7T3T8, Q7T3T9, Q7T3U0, Q7TNY7, Q7TP65, Q7TSX9, Q80SU3, Q80VM8, Q86XL3, Q8IVF5, Q8K3I4

Diamond homologs: P42570, Q5F259, Q6KAE5, Q86YJ7, Q99ME3, Q9Y6H5, B0G124, B4E2M5, C7B178, L7XCU0, O43150, O75762, O95271, P25631, P28492, P77736, Q01317, Q0VC93, Q10728, Q28FJ2, Q3KP44, Q3SX45, Q3UES3, Q3UMT1, Q3UX43, Q3V096, Q4R7L8, Q569N2, Q571F8, Q5EA33, Q5RD76, Q5SUE8, Q5U464, Q5ZLC6, Q5ZLC8, Q6AI12, Q6PFX9, Q6RI86, Q7SIG6, Q7XUW4

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
GSK3B	down-regulates	SNCAIP	phosphorylation
SIAH1	down-regulates	SNCAIP	ubiquitination
SIAH2	down-regulates	SNCAIP	ubiquitination
RNF19A	“up-regulates quantity”	SNCAIP	ubiquitination
PRKN	“up-regulates quantity by stabilization”	SNCAIP	ubiquitination
SNCAIP	up-regulates	Lewy_body_formation
SNCAIP	“up-regulates activity”	SNCA	binding
PRKN	“down-regulates quantity by destabilization”	SNCAIP	ubiquitination

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

162 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	112
Likely benign	21
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

2812 predictions. Top by Δscore:

Variant	Effect	Δscore
5:122391071:T:A	acceptor_gain	1.0000
5:122391192:G:GG	donor_gain	1.0000
5:122403778:T:TA	acceptor_gain	1.0000
5:122403779:G:A	acceptor_gain	1.0000
5:122403866:G:C	donor_loss	1.0000
5:122403867:T:A	donor_loss	1.0000
5:122444561:A:AG	acceptor_gain	1.0000
5:122444562:G:GA	acceptor_gain	1.0000
5:122444730:GGA:G	donor_gain	1.0000
5:122444731:GA:G	donor_gain	1.0000
5:122444731:GAG:G	donor_gain	1.0000
5:122444733:G:GG	donor_gain	1.0000
5:122449843:A:AG	acceptor_gain	1.0000
5:122449844:G:GG	acceptor_gain	1.0000
5:122449914:C:T	donor_gain	1.0000
5:122450531:A:AG	acceptor_gain	1.0000
5:122450532:G:GG	acceptor_gain	1.0000
5:122451589:A:T	donor_gain	1.0000
5:122451599:GCA:G	donor_gain	1.0000
5:122451602:G:GG	donor_gain	1.0000
5:122312282:CGGG:C	donor_loss	0.9900
5:122312283:GG:G	donor_gain	0.9900
5:122312284:GG:G	donor_gain	0.9900
5:122312285:G:GG	donor_gain	0.9900
5:122312285:GTG:G	donor_loss	0.9900
5:122312287:GAG:G	donor_loss	0.9900
5:122391077:T:TA	acceptor_gain	0.9900
5:122391088:GGA:G	acceptor_gain	0.9900
5:122391187:TATCT:T	donor_gain	0.9900
5:122391188:ATCT:A	donor_gain	0.9900

AlphaMissense

6021 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:122440648:T:C	L439P	1.000
5:122444666:T:C	L509P	1.000
5:122444683:T:C	C515R	1.000
5:122444685:C:G	C515W	1.000
5:122444693:T:C	L518P	1.000
5:122391154:T:C	L7P	0.999
5:122391160:T:C	L9S	0.999
5:122423180:T:C	L148P	0.999
5:122423195:T:C	I153T	0.999
5:122423195:T:G	I153S	0.999
5:122423198:T:C	L154P	0.999
5:122425455:T:C	L369P	0.999
5:122432027:T:C	L414P	0.999
5:122440644:T:A	W438R	0.999
5:122440644:T:C	W438R	0.999
5:122440651:T:C	L440P	0.999
5:122444570:T:A	V477D	0.999
5:122444588:T:A	V483D	0.999
5:122444618:C:A	P493H	0.999
5:122444630:C:A	A497D	0.999
5:122444662:T:G	Y508D	0.999
5:122444678:A:T	E513V	0.999
5:122444684:G:A	C515Y	0.999
5:122444693:T:A	L518Q	0.999
5:122444696:C:A	A519D	0.999
5:122444726:T:C	L529P	0.999
5:122391150:T:C	Y6H	0.998
5:122391154:T:A	L7H	0.998
5:122423180:T:A	L148H	0.998
5:122423195:T:A	I153N	0.998

dbSNP variants (sampled 300 via entrez): RS1000020335 (5:122340054 A>C), RS1000058532 (5:122321259 G>A,C), RS1000087296 (5:122454763 C>G,T), RS1000088377 (5:122387717 C>T), RS1000116011 (5:122454888 T>C), RS1000123068 (5:122405278 T>C), RS1000128954 (5:122333521 C>G), RS1000133384 (5:122345943 G>C), RS1000168526 (5:122413252 T>A), RS1000168674 (5:122416890 A>G), RS1000201707 (5:122417228 G>A), RS1000213723 (5:122461345 A>C), RS1000226212 (5:122364839 A>C), RS1000246746 (5:122393606 C>G), RS1000263109 (5:122448572 C>T)

Disease associations

OMIM: gene MIM:603779 | disease phenotypes: MIM:168600

GenCC curated gene-disease

Mondo (1): late-onset Parkinson disease (MONDO:0008199)

Orphanet (1): Hereditary late-onset Parkinson disease (Orphanet:411602)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000012	Urinary urgency
HP:0000298	Mask-like facies
HP:0000716	Depression
HP:0000726	Dementia
HP:0000738	Hallucinations
HP:0000751	Personality changes
HP:0001260	Dysarthria
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001621	Weak voice
HP:0002015	Dysphagia
HP:0002019	Constipation
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002172	Postural instability
HP:0002322	Resting tremor
HP:0002360	Sleep disturbance
HP:0002529	Neuronal loss in central nervous system
HP:0003581	Adult onset
HP:0003584	Late onset
HP:0003587	Insidious onset
HP:0003676	Progressive
HP:0003745	Sporadic
HP:0007311	Short stepped shuffling gait
HP:0011960	Substantia nigra gliosis
HP:0012332	Abnormal autonomic nervous system physiology
HP:0031908	Micrographia
HP:0100315	Lewy bodies

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002862_3	Mood disorder and prion disease	6.000000e-06
GCST003178_1	Event free survival in diffuse large B-cell lymphoma treated with immunochemotherapy	2.000000e-07
GCST003439_2	Response to paclitaxel in ovarian cancer (Caspase 3/7 EC50)	3.000000e-07
GCST005845_3	Heart rate increase in response to exercise	2.000000e-15
GCST005848_12	Heart rate response to recovery post exercise (50 sec)	1.000000e-09
GCST005851_24	Delirium	3.000000e-06
GCST009287_1	Chronic kidney disease (end stage renal disease vs. normal eGFR) in type 1 diabetes	1.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0000482	event free survival time
EFO:0007754	response to immunochemotherapy
EFO:0006952	cytotoxicity measurement
EFO:0009184	heart rate response to exercise
EFO:0009185	heart rate response to recovery post exercise

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1926494 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression	5
Valproic Acid	affects expression, increases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	increases methylation, decreases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
bisphenol A	decreases methylation	1
lead acetate	decreases expression	1
trichostatin A	increases expression	1
zinc chromate	decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
versicolorin A	decreases expression	1
cupric chloride	decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation	1
Calcitriol	increases expression	1
Methapyrilene	increases methylation	1
Nitrobenzenes	affects response to substance	1
Phthalic Acids	increases methylation	1
Progesterone	affects cotreatment, decreases expression	1
Smoke	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1931011	Binding	Binding affinity to human alpha-synphilin monomer expressed in Escherichia coli BL21 by fluorescence intensity assay	Synthesis and in vitro evaluation of fluorinated styryl benzazoles as amyloid-probes. — Bioorg Med Chem

Clinical trials (associated diseases)

12 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT01807481	PHASE4	UNKNOWN	Phase IV Study to Evaluate the Efficacy and Safety of Mircera in PD
NCT07015671	PHASE3	COMPLETED	Bioavailability and Bioequivalence Study of ER Torsemide and Spironolactone FDC Tablet in Healthy Subjects
NCT03942458	PHASE1	COMPLETED	Pharmacokinetics and Pharmacodynamics of Vicagrel in Healthy Adult Subjects of Different CYP2C19
NCT07195825	PHASE1	RECRUITING	A Clinical Study to Evaluate the Safety, and Tolerability of BBM-P002 in the Treatment of Parkinson’s Disease
NCT04093349	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Gene Transfer Study for Late-Onset Pompe Disease (RESOLUTE)
NCT07282847	PHASE1/PHASE2	RECRUITING	A Study to Evaluate Safety, Tolerability, and Efficacy of AB-1009 Gene Therapy (GAA Gene) in Adult Participants With Late Onset Pompe Disease (PROGRESS-GT LOPD)
NCT00105131	Not specified	COMPLETED	Genetic Characterization of Parkinson’s Disease
NCT03021408	Not specified	UNKNOWN	Effectiveness of Different Approaches for the Rehabilitation of Gait in Patients With Parkinson’s Disease
NCT03893240	Not specified	COMPLETED	Neutralizing Antibody Seroprevalence Study With a Retrospective Component in Participants With Late-Onset Pompe Disease
NCT05810454	Not specified	NOT_YET_RECRUITING	iPACES v3 MCI NIA Protocol Copied for iPACES v4 PD NINDS